Multipurpose prevention technologies that block HIV acquisition and pregnancy are urgently needed. We plan to develop a novel EVA (ethylene vinyl acetate) vaginal ring that releases two anti-HIV agents (1 of 2 novel NNRTIs and zinc acetate, ZA) and a low dose progestin only contraceptive (Levonorgestrel, LNG). EVA is the polymer used in the FDA-approved product NuvaRing; MIV-150 and MIV-160 are potent NNRTIs not used in current HIV treatments; ZA prevents SHIV-RT and HSV-2 infection in vivo; and LNG is the most widely used progestin in approved oral contraceptives (in combination with ethinyl estradiol or alone in low dose progestin only contraceptives). We have shown that repeated application of a ZA gel significantly protects macaques against SHIV-RT; a MIV-150/ZA combination gel is even more effective. Recent studies also revealed that EVA rings releasing either MIV-150 or MIV-160 protect macaques against SHIV-RT infection. We propose that combination of MIV-150 or MIV-160 with ZA in a vaginal ring will represent a potent and broad-acting sustained release microbicide. In addition, the WHO-sponsored Phase 3 trial with a vaginal ring releasing 20 mg/d of LNG showed it to be a highly effective contraceptive. We hypothesize that a vaginal ring releasing MIV-150 or MIV- 160, ZA, and LNG will be a novel microbicide/contraceptive drug delivery system that will prevent HIV and HSV-2 infection, as well as release sufficient amounts of LNG to prevent pregnancy. The combination of a potent NNRTI that is not used to treat HIV with ZA represents a unique antiviral strategy to limit drug resistance issues, which will ultimately arise with rings including only one drug against HIV (e.g. dapivirine/LNG or tenofovir/LNG). In the R21 phase of the application we will run in vitro and in vivo studies to determine if combinations of the neat and formulated APIs are stable and effective. Concurrently, we will manufacture EVA rings loaded with the three API combinations and measure release rates and API interactions over time. In the R33 phase, we will transfer the ring technology to a CRO to develop a robust process to manufacture optimized prototype rings. PK/PD, biomarker, and antiviral efficacy studies will be performed in macaques. The formulation chemistry (R21 and R33) and macaque testing (R33) will guide the decision of which NNRTI/ZA/LNG combination ring to move forward for scale up and future clinical testing. This proposal addresses a critical unmet medical need; reducing a woman's simultaneous risk of unplanned pregnancy and HIV/HSV-2, lowering both the number of unplanned pregnancies and deaths due to HIV and complications with pregnancy. PUBLIC HEALTH RELEVANCE: We plan to develop a safe and effective vaginal ring comprising two anti-HIV agents and a contraceptive to protect women from HIV, HSV-2, and unplanned pregnancy. We expect this unique ring will be more effective, particularly in limiting the spread of drug-resistant HIV, than products in development elsewhere that contain only one anti-HIV agent and a contraceptive.